Vitamin D is a recent arrival in the roster of agents that are known to regulate the immune system. Vitamin D is converted in a two-step process to the hormone, 1,25-dihydroxycholecalciferol (1,25-(OH)2D3)1 that is a key factor in regulating serum calcium, phosphorus and bone (DeLuca, 1997). This hormone acts in a steroid hormone-like mechanism through a nuclear receptor, the vitamin D receptor (VDR), which is a member of the steroid hormone receptor superfamily (Pike, 1991; Ross, et al., 1993). The discovery of VDR in peripheral blood lymphocytes (Bhalla, et al., 1983; Provvedini, et al., 1983) is a factor that led to the realization that 1,25-(OH)2D3 is a significant regulator of the immune system. The most striking evidence of a role for 1,25-(OH)2D3 as an immune system regulator comes from in vivo experiments. 1,25-(OH)2D3can prevent the development of EAE (Cantorna, et al., 1996 and U.S. Pat. No. 5,716,946; Lemire and Archer, 1991), experimental arthritis (Cantorna, et al., 1998a), and 1,25-(OH)2D3can markedly inhibit transplant rejection (Bouillon, et al., 1995; Hullett, et al., 1998).
1Abbreviations: central nervous system, CNS; 1,25-dihydroxycholecalciferol, 1,25-(OH)2D3; experimental autoimmune encephalomyelitis, EAE; glyceraldehyde-3-phosphate dehydrogenase, lymph node, LN; multiple sclerosis, MS; interferon xcex3, IFN-xcex3; interleukin-4, IL-4; transforming growth factor xcex21, TGF-xcex21; tumor necrosis factor-xcex1, TNF-xcex1; type-1 helper, Th1; type-2 helper, Th2; vitamin D receptor, VDR.
EAE is mediated by CD4+ T cells, which mount an inappropriate immune-mediated attack on the central nervous system (CNS). Type-1 helper (Th1) cells specific for CNS antigens induce the disease and the Th1 cytokines interferon (IFN)-xcex3 and tumor necrosis factor (TNF)-xcex1 are associated with EAE in mice (Holda and Swanborg, 1982; Powell, et al., 1990). Conversely, type-2 helper (Th2) cells and other cell types which produce interleukin (IL)-4 and transforming growth factor (TGF)-xcex21 in response to CNS antigens are known to ameliorate EAE. In vivo 1,25-(OH)2D3 treatments result in a net loss in the total number of lymphocytes and a net increase in the expression of IL-4 and TGF-xcex21 (Cantorna, et al., 1998b). Conversely the in vivo 1,25-treatments had no effect on IFN-xcex3 or TNF-xcex1 expression (Cantorna, et al., 1998b). The role, if any, for calcium in the regulation of the immune response remains unclear.
The present invention is a method of more effectively treating multiple sclerosis patients. The method comprises the step of administration of an amount of calcium that renders a vitamin D compound effective in preventing or markedly reducing MS symptoms. Preferably, this amount of calcium is 0.5-2 g per patient per day. Most preferably, the amount is between 1 and 2 g of calcium as a salt with a variety of anions, e.g. CO3=, PO 4=, Cl2xe2x88x92 acetate, gluconate, citrate, etc.
In one embodiment, the vitamin D compound is 1xcex1,25-dihydroxyvitamin D3 (1,25-(OH)2D3), 19-nor-1,25-dihydroxyvitamin D2 (19-nor-1,25-(OH)2D3), 24-homo-22-dehydro-22E-1xcex1,25-dihydroxyvitamin D3 (24-homo-22-dehydro-22E-1,25-(OH)2D3), 1,25-dihydroxy-24(E)-dehydro-24-homo-vitamin D3 (1,25-(OH)2-24-homo D3), or 19-nor-1,25-dihydroxy-21-epi-vitamin D3 (19-nor-1,25-(OH)2-21-epi-D3). In a most preferred form of the invention, the compound used is 1,25(OH)2D3.
In another embodiment, the present invention is a pharmaceutical composition comprising an amount of vitamin D and an amount of calcium that renders the vitamin D compound more effective in reducing the multiple sclerosis symptoms.
It is an object of the present invention to more effectively diminish multiple sclerosis symptoms in a multiple sclerosis patient.
It is another object of the present invention to reduce the amount of vitamin D compound needed to alleviate MS symptoms.
Other features, advantages and objects of the present invention will become apparent to one of skill in the art after review of the specification, claims and drawings.